Epidemiology, Diagnosis, and Treatment of Melanoma - Assignment Example

MELANOMA A melanoma is defined as a malignant tumor that originates from a melanocyte, a specialized type of cell containing the pigment melanin. Although the vast majority of melanomas are found in the skin, they are also seen in the eye and the bowel. They vary in their aggressive behavior; although they are the most lethal skin cancers and responsible for 70% of the deaths associated with skin cancer. They are more often seen in the Caucasian population, are more frequently in males. According to a WHO report in 2006, 48,000 melanoma related deaths occur every year. Types of Melanoma - Histological classification According to the histological subtypes, melanomas can be classified according to the ICD-O (International Classification of Diseases - Oncologic) published by the WHO in 2000. They are : (a) Superficial spreading melanoma (SSM) - The commonest subtype, and has a reasonably good prognosis. (b) Lentigo maligna melanoma (LMM) - A Much less common type, formed from the degeneration of a precursor skin lesion called the lentigo maligna. (c ) Acral lentigous melanoma - Seen on the soles and feet, and can be either SSM or NM. (d) Nodular melanoma (NM) - They represent a third of all melanomas diagnosed in Caucasians. Its growth is vertically downwards through the skin from an early phase, resulting in a poor prognosis. Some authors refer to a polypoidal melanoma, which is a variant of melanoma with a nodule above the skin. Epidemiology of Melanoma Epidemiological studies have indicated that theer are two groups of factors responsible for melanoma - environmental (extrinsic) and genetic (intrinsic). Exposure to ultraviolet rays (UVA & UVB) rank as the most important factors for development of melanomas. This effected through DNA damage, specifically thymine dimerization leading to oncogenic mutations. It is well known that the incidence of melanoma in Queensland, Australia (50/100,000) is five times that of the UK (10,000), despite the fact that the nearly all cases in Australia occur in people of Scottish and Irish descent. This clearly points out to solar exposure as the prime factor in it causation. Although tanning beds (Berwick 507) and sunscreens have been implicated as a possible causative factor, no significant statistical evidence has been presented yet. Additional risk is also seen in red-headed and fair-skinned people, people with multiple dysplastic or atypical naevi, and in a condition called congenital giant melanocytic naevi. A family history of melanoma greatly increases the chances of a malignant melanoma. In addition, the presence of one melanoma greatly increases the risk of a second primary tumour. Genetics of Melanoma. 1. Germline Mutations : Apart from the fact that melanoma clusters can be seen in certain families, and melanoma-prone families are well known to have mutations in CDKN2A, CDK4 and other genes. The p16 gene mutation has also been reported in over 25% of familial melanomas worldwide, as well as in about 10 % of sporadic melanomas. It has a low degree of penetrance, and it is likely that sporadic melanoma has a complex pattern of inheritance. Melanoma also has an association with various cancer family syndromes, most notably pancreatic cancer, but also in breast, throat and gastro-intestinal cancers. 2. Somatic mutations : A genetic progression model of the step-by-step transformation of precursor lesions (naevi) to melanomas, or the stages of melanoma progression itself have shown that there are important genetic loci where were changes accumulate. They are mostly due to loss of chromosomal material on multiple loci : chromosomes 1,3,6,9,10,11 and 17 being particularly affected. Somatic mutations on the BRAF gene has also been described in up to 60 % of melanomas. 3. The genetics of the at-risk phenotype : Over the past two decades, as it has become clearer that the fair skin-type and high naevus counts are powerful predictors of melanoma, the hunt for susceptible genes in these at-risk phenotypes has begun. In addition, the propensity to get sunburns as a result of solar exposure in fair skin/hair types has also been shown to be an important risk factor. Although a higher degree of p16 penetrance has been described in these individuals, no definite genetic changes have been described. The MC1R locus with a large number of polymorphic variants has been a subject of intense studies, but the relationship is quite complex. With this background in mind, we would now look at the current research on melanomas. Current research Today, only 11 % of patients with melanoma have a fatal outcome, compared to 60 % in the 1960's. (Demierre 1728). Apart from the traditional risk factors elucidated above recent research has also shown an increased melanoma risk for renal transplant recipients. (Demiere 1729). A recent meta-anlaysis heas also shown that Vitamin D receptor (VDR gene) polymorphisms are also related to the risk of melanoma. (Mocellin 2398). This implies that sun exposure, through the activation of the Vitamin D system, can exert an anti-melanoma effect which might be reduced with certain genotypes, resulting in an enhanced risk of melanoma development. This paper identifies the Bsml polymorph as that with the highest risk of melanoma development and hints that future prevention/treatment strategies might incorporate the anti-cancer effects of Vitamin D. Another promising line of enquiry into the protective mechanisms that limit UV-radiation induced DNA damage, and possibly initiation of melanoma transformation, is understanding the role of p53-dependant alpha-MSH regulation. P53 is a tumor suppressor gene in this respect, and has several other dependant roles in the process of cellular growth and regulation. (Gaitonde 148) Other authors, however have urged caution before accepting p53 as central to the process of protection of melanocytes from UV radiation, and ultimately preventing melanoma initiation. (Slominski 307). Another promising line of current melanoma research is based on understanding the transcription factors and regulation of growth and differentiation of melanoma cell lines. The POU domain has been reported to be one of the most important with regard to transcription factors in melanoma, and BRN-2 is a factor which leads to survival and proliferation of metastatic malignant melanomas. (Cook). Signalling pathways inside the cell are also another extremely important group of processes which are deranged in malignant cells, and can potentially be targeted for controlling cell growth. In the melanoma cells, the four major signaling abnormalities have been - -catenin deregulation (mutation/mislocalization), p16 loss, MAP kinase activation, and Akt activation. Recently, the fourth pathway, Akt activation has been shown to be directly related to reactive oxygen (superoxide) often transforming the behavior of the tumor by exhibiting aggressive vertical growth and promoting metastasis. (Fried 117) In addition, this knowledge about the role and effect of reactive oxygen is likely to provide the basis of novel therapies for controlling the aggressive behavior of melanomas, and also provide laboratory markers that can be used for therapy. It is also possible that like leukemias, in the future, a classification system based on markers can be devised. The spectrum of genes controlling pigmentation of cells and hair has also undergone rapid expansion in recent years. About 100 such genes have been discovered in mice, of which 50 have human homologues. These new insights into pigment cell regulation have come from genome wide association studies (GWAS), which open the door for more sophisticated analyses of melanoma cancer risk etiology. (Bastian 507). Between 2007 and 2008, the paper list five newly described loci, leading to a fundamental shift in our understanding of the polymorphic nature of pigment cell regulation. In the future this will have a massive impact on our understanding and treatment of melanomas. The search for a malignant melanoma stem cell (MMSC) is integral to our efforts to describe a model of tumor progression for the malignant melanoma. Although still putative, several models have been put forward for identifying such a precursor cell. (Schatton 39). Mechanisms of melanoma growth and differentiation, its metastatic potential, and the causes of resistance to chemotherapeutic agents can all be better elucidated by such an understanding leading to novel treatment regimes in the future. Data-mining of DNA microarrays, an essential bioinformatics tool, is a different approach to identify important genetic changes in the progression of tumors, and retrospective identify important genetic sequences in this process. In the case of melanoma, although extensive gene lists with important changes have been found (Hoek 466) associated with practically all aspects of growth, signaling and functioning of the melanoma cell, we have yet to underpin the initiating sequences which could yield potential therapeutic strategies. At best , they describe an array of genetic abnormalities that exist in melanoma cells. Despite this many authors (Baxter et al 201) remain convinced that although laborious, an informatic and genomic analysis of melanocyte gene libraries would eventually help us in thoroughly understanding melanocyte development, functioning and its role in diseases like the melanoma, and pave the way for future discoveries of new genes and therapeutic targets. Transgenic melanoma models in animals are in the process of development, and could be used more extensively in future for therapeutic trials for newer agents in the treatment of melanoma, in addition to understanding the progression models better. (Larue 485). The invasiveness of melanoma cells has also been the focus of a lot of current research. Recent research has focused on a tumor cell's (melanoma) interaction with surrounding keratinocyttes and fibrocytes, enabling them to acquire adhesiveness and spread from its original location. (Gaggioli 165). In addition this paper also describes the role of VEG-A and VEG-F, which are vascular endothelial growth factors crucial for the regulation and organization of the blood supply to allow melanoma growth. In future, exploiting these factors could well become the basis of new therapeutic strategies. Epigenetic events, which are currently an important aspect of modern genetic studies, involve changes in phenotypes which are not brought about by a change in DNA sequence. It is currently thought that they are at least as important as traditional events e.g. mutations leading to oncogene activation or disruption of tumor suppression gene activity. They involve changes in the packaging or functioning od DNA as a result of processes like methylation, or chromatin re-organization. Although at present they are highly complex and not fully understood, recent research (Rothhammer 92) in melanomas have highlighted numerous additional pathways for melanoma pathogenesis and progression. Finally, although wide surgical excision remains the only method of cure for melanomas, newer methods of therapy are being tried out ( Melnikova 505) particularly in resistant cases. It is becoming clear that targeting of several pathways controlling growth or cell regulation (e.g. apoptosis, nitric oxide, VEG-F or VEG-A, etc) are required, with antibodies or novel agents. In the near future a wealth of clinical research data will continue to emerge in the understanding and treatment of melanoma, an intriguing disorder. References Bastian B, Pinkel D. "Expanding the genetic spectrum of pigmentation." Pigment Cell & Melanoma Research, 2008 August, Volume 21, Issue 5, Pages 507-508 Berwick M. "Are tanning beds "safe" Human studies of melanoma." Pigment Cell & Melanoma Research, 2008. Volume 21, Issue 5, Pages 517-519 Baxter LL, Hsu BJ, Lowell U et al. "Informatic and genomic analysis of melanocyte cDNA libraries as a resource for the study of melanocyte development and function." Pigment Cell & Melanoma Research, 2007, Volume 20 Issue 3,Pages201-209. Cook A, Sturm R. "POU domain transcription factors: BRN2 as a regulator of melanocytic growth and tumourigenesis." Pigment Cell & Melanoma Research, 2008 September; published online at : http://dx.doi.org/10.1111/j.1755-148X.2008.00510.x. (Current Impact Factor 4.3) Demierre MF, Sabel MS, Margolin KA, Daud AI, Sondak VK. "State of the science 60th anniversary review: 60 Years of advances in cutaneous melanoma epidemiology, diagnosis, and treatment, as reported in the journal Cancer." Cancer. 2008 Oct 1;113(7 Suppl):1728-43. Fried L, Arbiser J. "The reactive oxygen-driven tumor: relevance to melanoma." Pigment Cell & Melanoma Research, 2008, Volume 21, Issue 2, Pages 117-122 Gaggioli C, Sahai E. "Melanoma invasion - current knowledge and future directions." Pigment Cell & Melanoma Research, 2007, Volume 20 Issue 3,Pages161-172 Gaitonde S, Ronai Z. "A darker side to p53." Pigment Cell & Melanoma Research, 2007. Volume 20, Issue 3, Pages 148-149 Hoek K S. "DNA microarray analyses of melanoma gene expression: a decade in the mines." Pigment Cell & Melanoma Research, 2007, December, Volume 20, Issue 6, Pages 466-484 Larue L, Beerman F. "Cutaneous melanoma in genetically modified animals." Pigment Cell & Melanoma Research, 2007, December, Volume 20, Issue 6, Pages 485-497 Melnikova V O, Menashe B. "Searching for the Achilles' heel of melanoma cells: new treatment modalities." Pigment Cell & Melanoma Research, 2007. Volume 21, Issue 5, Pages 505-506 Mocellin Simone , Nitti Donato . "Vitamin D receptor polymorphisms and the risk of cutaneous melanoma". Cancer. 2008 Volume 113 Issue 9,Pages2398-2407 Rothhammer T, Bosserhoff A. "Epigenetic events in malignant melanoma." Pigment Cell & Melanoma Research, 2007. Volume 20, Issue 2, Pages 92-111 Schatton T, Frank MH. "Cancer stem cells and human malignant melanoma." Pigment Cell & Melanoma Research, 2008, Volume 21, Issue 1, Pages 39-55 Slominski A, Tobin D J, "Does p53 regulate skin pigmentation by controlling proopiomelanocortin gene transcription" Pigment Cell & Melanoma Research, 2007, Volume 20, Issue 4, Pages 307-308 *** Read More